Regulation of TGF-β ligand and receptor expression in neonatal rat lungs exposed to chronic hypoxia

Vicencio, Alfin G.; Eickelberg, Oliver; Stankewich, Michael C.; Kashgarian, Michael; Haddad, Gabriel G.

doi:10.1152/japplphysiol.00031.2002

Cited by 52 publications

(39 citation statements)

References 36 publications

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“…In addition, β‐arrestin2 promotes the endocytosis of TGFβR3, and TGFβR3 and β‐arrestin2 coordinately function to regulate epithelial and cancer cell migration 22. Interestingly, TGFβR3 expression is significantly suppressed in rat lungs during long‐term anoxia (day 14) 23. In contrast, our results suggest that TGFβR3 is upregulated in mice during MI.…”

Section: Discussionmentioning

confidence: 67%

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Sun

Duan

et al. 2017

JAHA

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BackgroundMyocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor‐β receptor III (TGFβR3) on cardiomyocyte apoptosis during MI.Methods and ResultsAn MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFβR3, and mitogen‐activated protein kinase signaling were assessed by methylthiazolyldiphenyl‐tetrazolium bromide assay, terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFβR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGFβR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFβR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFβR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFβR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFβR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFβR3 by adeno‐associated viral vector serotype 9–TGFβR3 short hairpin RNA attenuated the effects of MI in mice.Conclusions TGFβR3 promotes apoptosis of cardiomyocytes via a p38 pathway–associated mechanism, and loss of TGFβR3 reduces MI injury, which suggests that TGFβR3 may serve as a novel therapeutic target for MI.

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Section: Discussionmentioning

confidence: 67%

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Sun

Duan

et al. 2017

JAHA

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“…Hemodynamic measurements are difficult, and isolation of pulmonary vascular cells from newborn mice for investigation of cellular mechanisms is technically challenging. Chronic hypoxic exposure in the developing animal (unlike the adult animal) leads to growth retardation, and concomitant impairment of lung alveolar development (and lung vascular growth) may occur (28,29). However, it is not possible to determine what degree of remodeling is directly due to hypoxia per se and how much is due to growth restriction induced by hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-A Receptor Blockade Prevents and Partially Reverses Neonatal Hypoxic Pulmonary Vascular Remodeling

et al. 2005

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Hypoxia-induced pulmonary vascular remodeling (HPVR) may lead to persistent pulmonary hypertension of the newborn or cor pulmonale. Endothelin-1 (ET-1), via endothelin-A (ET A ) receptor activation, mediates hypoxic pulmonary vasoconstriction. Our objectives were to develop a newborn mouse model of HPVR and to test the hypothesis that ET A blockade would prevent and reverse HPVR in this model. C57BL/6 mice (n ϭ 64) were exposed to 12% oxygen (HYP group) or room air (RA group) from birth to 2 wk of age. The mice were injected intraperitoneally daily with either BQ-610 (ET A blocker) or vehicle (cottonseed oil) from birth (prevention study) or from 6 d of age (reversal study). HPVR was assessed histologically by pulmonary vascular morphometry by an examiner masked to study group, and by measurement of the right ventricle to left ventricle (RV/LV) thickness ratio. Hypoxia increased medial wall thickness (%WT) in pulmonary arteries Ͻ100 m in diameter and RV/LV thickness ratio. BQ-610 prevented the hypoxiainduced increase in %WT and RV/LV thickness ratio when given from birth, and later therapy partially reversed the hypoxiainduced increase in %WT but not RV/LV thickness ratio. These data show that in the newborn mouse model, chronic hypoxia leads to HPVR that can be completely prevented and partially reversed by ET A blockade. These results indicate that ET-1, acting via ET A receptors, is a mechanism of pathophysiologic significance underlying neonatal HPVR. Development of this newborn mouse model of HPVR facilitates investigation of mechanisms underlying this important and severe disease entity in human infants. In human neonates, chronic hypoxemia increases muscularity of the pulmonary arteries and extends muscularity to more distal arteries (1). Fetal (2) and neonatal (3,4) hypoxemia also leads to pulmonary vascular remodeling in animal models. This pulmonary vascular remodeling may predispose to pulmonary vasoconstriction and PPHN in response to normal changes in oxygenation and acid-base status occurring during labor and early neonatal life. PPHN affects more than 10,000 infants every year in the United States (5) and is associated with considerable morbidity and mortality. Disorders such as bronchopulmonary dysplasia that affect extremely premature newborn infants are also associated with elevated pulmonary arterial pressures and pulmonary vascular remodeling (6). Congenital heart diseases associated with hypoxemia and/or increased pulmonary blood flow may also result in hypoxia-or high flow-induced pulmonary vascular remodeling (7,8). In a newborn piglet model, increased vascular smooth muscle tone was the primary cause of elevated pulmonary pressure following 3-5 d of hypoxia exposure, while with longer hypoxia exposure (10 -12 d), structural changes in the pulmonary arteries contributed to the elevated pulmonary arterial pressure (4).ET-1 is a 21-amino acid polypeptide with strong vasoactive properties that acts via two major receptor isoforms in the vascular bed, ET A and ET B . In the pulmonary artery, E...

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“…It has also been reported that chronic hypoxia can influence TGF-␤ ligand and receptor expression (51), and that very low birth weight infants receiving oxygen therapy exhibit elevated TGF-␤ levels in endotracheal aspirates (24). Thus we suspected that oxygen supplementation may influence TGF-␤/BMP signaling in the neonatal lung.…”

mentioning

confidence: 85%

Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia

Alejandre-Alcázar

Kwapiszewska²,

Reiss³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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207

128

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-Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-␤ and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O2 between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O2, and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF-␤ type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-␤ signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O2 as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O2. After exposure to 85% O2, primary alveolar type II cells were more susceptible to TGF-␤-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O2 significantly enhanced the TGF-␤-stimulated production of the ␣1 subunit of type I collagen (I␣1), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-␤/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.

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Regulation of TGF-β ligand and receptor expression in neonatal rat lungs exposed to chronic hypoxia

Cited by 52 publications

References 36 publications

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

Endothelin-A Receptor Blockade Prevents and Partially Reverses Neonatal Hypoxic Pulmonary Vascular Remodeling

Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia

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